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Erythropoiesis-stimulating agents (ESAs) are approved as an alternative to blood transfusions for treating anemia secondary to chemotherapy in patients with cancer. Recently, ESAs have been a source of controversy and confusion in the oncology community. This began when two European trials--the Breast Cancer Erythropoietin Survival Trial (BEST) and the Advanced Head-and-Neck Cancer Treated with Radiotherapy (ENHANCE) Study--raised safety concerns about decreased overall survival and increased venous thromboembolic events. In 2004, the United States Food and Drug Administration (FDA) convened its Oncologic Drugs Advisory Committee (ODAC) to review the data and reassess the risks and benefits of ESAs in patients with cancer. On May 10, 2007, ODAC reconvened when five trials (BEST, ENHANCE, AMG-20010103, AMG-20000161, and EPO-CAN-20) showed decreased overall survival. The briefing document noted that studies demonstrating detrimental effects on survival and/or tumor outcomes used an unapproved treatment regimen designed to maintain hemoglobin levels above 12 g/dl. On May 14, 2007, just days after the ODAC reconvened, the Centers for Medicare and Medicaid Services (CMS) released a proposed decision memo for a national coverage determination (NCD) imposing restrictions on ESAs. For health care providers, aspects of the proposed NCD were markedly inconsistent with FDA-approved ESA use and generally were considered ambiguous and unclear. Over objections of several professional associations and members of Congress, on July 30, 2007, CMS posted the final NCD and declared it effective immediately. When compared with FDA-approved labeling and professional society guidelines, the NCD revealed differences in ESA initiation, dosage escalation, dosage reduction, and definition of response. These discrepancies have generated confusion among health care providers, who are struggling over whether they can feasibly provide a dual system of care--one for Medicare patients and another for non-Medicare patients--that is evidence based. With this supplement, we hope to educate health care providers on the issues and challenges associated with policy-guided health care when discrepancies exist between the policy and evidence-based practice; offer guidance on implementing the NCD; and highlight the important role of pharmacists in the process. [ABSTRACT FROM AUTHOR]

Reprints an article entitled `Death Becomes Them,' published in the November 21, 1998 issue of `The Spectator,' about the practice of euthanasia in Europe. Comments from Ben Zylic, campaigner against euthanasia; Perspective of euthanasia practitioner Pieter Admiraal; Legislative developments.

Competing Interests: Declarations of interests IG received support from Fundacion de Investigacion sanitaria and was cofunded by Instituto Carlos III for the present manuscript; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Gilead Sciences, Intercept, and AbbVie; and support for attending meetings or travel from Intercept and Gilead Sciences. EB received grants or contracts from Gilead Sciences; received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Gilead Sciences and Novo Nordisk; and participated on Data Safety Monitoring Boards or advisory boards for Bristol Myers Squibb, Boehringer Ingelheim, Gilead Sciences, Intercept, Inventiva, and Novo Nordisk. MC received grants or contracts and support for attending meetings or travel from the OECD programme of work for public health. RF received grants or contracts from Gilead Sciences, AbbVie, Roche, and Merck Sharp & Dohme; consulting fees from Gilead Sciences, AbbVie, Janssen, and Pfizer; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Gilead Sciences, AbbVie, Merck Sharp & Dohme, and AdamedPG; and support for attending meetings or travel from Gilead Sciences, AbbVie, and Merck Sharp & Dohme. JVL received grants or contracts from AbbVie, Gilead Sciences, Merck Sharp & Dohme; and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AbbVie, Gilead Sciences, Intercept, Janssen, and Merck Sharp & Dohme. AL received grants or contracts from the OECD programme of work for public health, which is supported by Ministries of Health, National Governmental Institutions, and intergovernmental organisations, as well as support to present results from OECD analyses to meetings, seminars, and workshops. CL received grants or contracts from the University of Oxford, UK National Centre for Smoking Cessation and Training, and Horizon 2020 of the European Commission; received royalties or licenses from and has patents planned, issued, or pending with Olvos Science (Cretan Iama); received payment for expert testimony from WHO and the European Commission; and participated on Data Safety Monitoring Boards or advisory boards for Merck Sharp & Dohme, Pfizer Hellas, Vianex. MPM received grants or contracts from AbbVie, Eiger BioPharmaceuticals, Bristol Myers Squibb, Dr Falk Pharma, Gilead Sciences, Intercept, Merck Sharp & Dohme, and Roche; received consulting fees from AbbVie, Bristol Myers Squibb, Dr Falk Pharma, Gilead Sciences, Intercept, Merck Sharp & Dohme, Novartis, and Roche; received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AbbVie, Bristol Myers Squibb, Dr Falk Pharma, Gilead Sciences, Merck Sharp & Dohme, and Roche; received support for attending meetings or travel from AbbVie, Bristol Myers Squibb, Dr Falk Pharma, Gilead Sciences, Merck Sharp & Dohme, and Roche; participated on Data Safety Monitoring Boards or advisory boards for Eiger, Dr Falk Pharma, Gilead Sciences, and Roche; and is Associate Editor for Clinical Gastroenterology and Hepatology. NKM received grants or contracts from Merck Sharp & Dohme and Gilead Sciences. MN received grants or contracts from Gilead Sciences, Merck Sharp & Dohme, AbbVie, and Janssen; and was President of the World Hepatitis Alliance (2018–20). CYP received grants or contracts from Takeda, Pliant, and Gilead Sciences; consulting fees from Pliant and Shire (Takeda); and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Takeda, Tillotts Pharma, and Pfizer. BSa received grants or contracts from Bristol Myers Squibb and Sirtex Medical; received consulting fees from Adaptimmune, AstraZeneca, Bayer, Bristol Myers Squibb, BTG, Sirtex Medical, TERUMO, H3 Biomedicine, Incyte, Ipsen, Lilly, and Roche; received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Bayer, Bristol Myers Squibb, Sirtex Medical, TERUMO, Incyte, and Ipsen; and participated on Data Safety Monitoring Boards or advisory boards for Adaptimmune, AstraZeneca, Bayer, Bristol Myers Squibb, BTG, Sirtex Medical, TERUMO, H3 Biomedicine, Incyte, Ipsen, Lilly, and Roche. CS received grants or contracts from BiomX and Galapagos; consulting fees from BiomX; and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Falk Foundation. NSc received grants or contracts from Gilead Sciences. MS-B received grants or contracts from the European Commission. CT received grants or contracts from Merck Sharp & Dohme; and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Gilead Sciences and AbbVie. RB received consulting fees from WHO. HC-P received consulting fees from Orphalan; and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Orphalan, Novo Nordisk, GENFIT, Promethera Biosciences, and Intercept. GD received consulting fees from Aligos Therapeutics, Roche, Arbutus Biopharma, Gilead Sciences, Shionogi, Antios Therapeutics; received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Gilead Sciences; and participated on Data Safety Monitoring Boards or advisory boards for Janssen, Pharmaceuticals, GlaxoSmithKline, and Aligos Therapeutics. THK received consulting fees from Engitix and Intercept; has stock or stock options in Ultimovacs; received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Gilead Sciences, Novartis, and AlfaSigma; and is on the board of the Biomedical Alliance in Europe. ES received consulting fees from Albireo, Mirum, and Alexion; received support for attending meetings or travel from Astellas; participated on Data Safety Monitoring Boards or advisory boards for Albireo, Alexion, and Mirum; and received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Albireo. PB received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Kedrion Biopharma, Biotest, and Chiesi Farmaceutici. MB received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Gilead Sciences and AbbVie. SJH received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Gilead Sciences. NF participated on Data Safety Monitoring Boards or advisory boards for Intercept in relation to NAFLD. GM participated on Data Safety Monitoring Boards or advisory boards for Gilead Sciences, Novartis, Pfizer, and AstraZeneca. All other authors declare no competing interests.

Food allergy affects up to 6% of Europeans. Allergen identification is important for the risk assessment and management of the inadvertent presence of allergens in foods. The VITAL® initiative for voluntary incidental trace allergen labeling suggests protein reference doses, based on clinical reactivity in food challenge studies, at or below which voluntary labelling is unnecessary. Here, we investigated if current analytical methodology could verify the published VITAL® 2.0 doses, that were available during this analysis, in serving sizes between 5 and 500 g. Available data on published and commercial ELISA, PCR and mass spectrometry methods, especially for the detection of peanuts, soy, hazelnut, wheat, cow's milk and hen's egg were reviewed in detail. Limit of detection, quantitative capability, matrix compatibility, and specificity were assessed. Implications by the recently published VITAL® 3.0 doses were also considered. We conclude that available analytical methods are capable of reasonably robust detection of peanut, soy, hazelnut and wheat allergens for levels at or below the VITAL® 2.0 and also 3.0 doses, with some methods even capable of achieving this in a large 500 g serving size. Cow's milk and hen's egg are more problematic, largely due to matrix/processing incompatibility. An unmet need remains for harmonized reporting units, available reference materials, and method ring-trials to enable validation and the provision of comparable measurement results., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background & Aims: GALAD and BALAD-2 are statistical models for estimating the likelihood of the presence of hepatocellular carcinoma (HCC) in individual patients with chronic liver disease and the survival of patients with HCC, respectively. Both models use objective measures, particularly the serum markers α-fetoprotein (AFP), AFP-L3, and des-γ-carboxyprothrombin. We aimed to validate these models in an international cohort of patients with HCC and assess their clinical performance., Methods: We collected data on cancer diagnosis and outcomes of 6834 patients (2430 with HCC and 4404 with chronic liver disease) recruited from Germany, Japan, and Hong Kong. We also collected data from 229 patients with other hepatobiliary tract cancers (cholangiocarcinoma or pancreatic adenocarcinoma) and 92 healthy individuals (controls). For reference, the original UK cohort (on which the GALAD model initially was built and BALAD-2 was validated) was included in the analysis. We assessed the effects of tumor size and etiology on GALAD model performance, and its ability to correctly discriminate HCC from other hepatobiliary cancers. We assessed the performance of BALAD-2 in patients with different stages of HCC., Results: In all cohorts, the area under the receiver operating characteristic curve (AUROC), quantifying the ability of GALAD to discriminate patients with HCC from patients with chronic liver disease, was greater than 0.90-similar to the series on which the model originally was built (AUROC, 0.97). GALAD discriminated patients with HCC from those with other hepatobiliary cancers with an AUROC value of 0.95; values were slightly lower for patients with small unifocal HCCs, ranging from 0.85 to 0.95. Etiology and treatment of chronic viral hepatitis had no effect on the performance of this model. BALAD-2 analysis assigned patients with HCC to 4 distinct prognostic groups-overall and when patients were stratified according to disease stage., Conclusions: We validated the performance of the GALAD and BALAD-2 models for the diagnosis of HCC and predicting patient survival, respectively (based on levels of the serum markers AFP, AFP-L3, and des-γ-carboxyprothrombin), in an international cohort of almost 7000 patients. These systems might be used in HCC surveillance and determination of patient prognosis., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Hepatocellular carcinoma (HCC) is the second most common cause of cancer deaths worldwide. The global HCC BRIDGE study was a multiregional, large-scale, longitudinal cohort study undertaken to improve understanding of real-life management of patients with HCC, from diagnosis to death., Methods: Data were collected retrospectively from January 2005 to September 2012 by chart reviews of eligible patients newly diagnosed with HCC at participating institutions., Results: Forty-two sites in 14 countries contributed final data for 18 031 patients. Asia accounted for 67% of patients, Europe for 20% and North America for 13%. As expected, the most common risk factor was hepatitis C virus in North America, Europe and Japan, and hepatitis B virus in China, South Korea and Taiwan. The most common Barcelona Clinic Liver Cancer stage at diagnosis was C in North America, Europe, China and South Korea, and A in Taiwan and Japan. Across all stages, first HCC treatment was most frequently transarterial chemoembolization in North America, Europe, China and South Korea, percutaneous ethanol injection or radiofrequency ablation in Japan and resection in Taiwan. Survival from first HCC treatment varied significantly by region, with median overall survival not reached for Taiwan and 60, 33, 31, 24 and 23 months for Japan, North America, South Korea, Europe and China respectively (P < 0.0001)., Conclusions: Initial results from the BRIDGE study confirm previously reported regional trends in patient demographic characteristics and HCC risk factors, document the heterogeneity of treatment approaches across regions/countries and underscore the need for earlier HCC diagnosis worldwide., (© 2015 The Authors. Liver International Published by John Wiley & Sons Ltd.)

Biologics are essential to oncology care. As patents for older biologics begin to expire, the United States is developing an abbreviated regulatory process for the approval of similar biologics (biosimilars), which raises important considerations for the safe and appropriate incorporation of biosimilars into clinical practice for patients with cancer. The potential for biosimilars to reduce the cost of biologics, which are often high-cost components of oncology care, was the impetus behind the Biologics Price Competition and Innovation Act of 2009, a part of the 2010 Affordable Care Act. In March 2011, NCCN assembled a work group consisting of thought leaders from NCCN Member Institutions and other organizations, to provide guidance regarding the challenges health care providers and other key stakeholders face in incorporating biosimilars in health care practice. The work group identified challenges surrounding biosimilars, including health care provider knowledge, substitution practices, pharmacovigilance, naming and product tracking, coverage and reimbursement, use in off-label settings, and data requirements for approval.

Using DNA extracted from a finger bone found in Denisova Cave in southern Siberia, we have sequenced the genome of an archaic hominin to about 1.9-fold coverage. This individual is from a group that shares a common origin with Neanderthals. This population was not involved in the putative gene flow from Neanderthals into Eurasians; however, the data suggest that it contributed 4-6% of its genetic material to the genomes of present-day Melanesians. We designate this hominin population 'Denisovans' and suggest that it may have been widespread in Asia during the Late Pleistocene epoch. A tooth found in Denisova Cave carries a mitochondrial genome highly similar to that of the finger bone. This tooth shares no derived morphological features with Neanderthals or modern humans, further indicating that Denisovans have an evolutionary history distinct from Neanderthals and modern humans.

Background: The genetic basis of susceptibility to hepatocellular carcinoma (HCC) is poorly understood. Genomic DNA was available from 98 patients with HCC, 77 familial controls, 97 controls from Hong Kong and 96 Northern European controls (NECs)., Methods: Polymorphisms of interleukin (IL)-1beta; IL-1 receptor antagonist (IL-1RN); IL-10 promoter (positions -1082, -819, and -592); and tumor necrosis factor (TNF)-alpha promoter (TNF-a -238 and -308) were investigated., Results: There was marked restriction in the distribution of the IL-1beta and IL-1RN genotypes among Chinese subjects with a predominance of the IL-1beta*1,1 and IL-1RN*1,1 (for unrelated controls compared with NECs only for IL-1beta: chi2 = 15.32, Pc = 0.000091 and for IL-1RN: chi2 = 16.08, Pc = 0.000061). For IL-10, the distribution of alleles was reversed in Chinese vs NECs. The TNFA*2 allele (TNFA -308 A), which is associated with high TNF-alpha production both in vivo and in vitro, was found in <10% of Chinese but was present in 33% of NECs (chi2 = 21.52, Pc <0.0000035)., Conclusion: Though this study failed to highlight specific associations between any of the polymorphisms tested and the HCC in Hong Kong Chinese, the differences in the distribution of tested alleles may, in part, account for the increased susceptibility of the Chinese population to develop HCC.